In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody

Overexpression of epidermal growth factor receptor (EGFR) has been correlat ed with tumor resistance to cytotoxic agents, including radiation (T, Akimo to et at, Clin, Cancer Res., 5: 2884-2890, 1999), and thus is a candidate t arget for anticancer treatment. This study investigated whether treatment w ith C225 anti-EGFR antibody would improve tumor response to radiotherapy. N ude mice bearing S-mm-diameter A431 tumor xenografts in the hind leg mere t reated with C225 antibody, 18 Gy of single-dose local tumor irradiation, or both. C225 was given i.p. at a dose of 1 mg/mouse 6 h before irradiation o r 6 h before and 3 and 6 days after irradiation. Delay in tumor growth was the treatment end point. C225 dramatically improved the efficacy of local t umor irradiation, particularly when multiple injections of C225 were admini stered. Tumor radioresponse was enhanced by a factor of 1.59 by a single do se and by a factor of 3.62 by 3 doses of C225. Histological analyses of tum ors revealed that C225 caused a striking increase in central tumor necrosis associated with hemorrhage and vascular thrombosis when combined with radi otherapy. In addition, C225 induced heavy tumor infiltration,with granulocy tes, increased tumor cell terminal differentiation, and inhibited tumor ang iogenesis. We conclude that C225 anti-EGFR antibody enhances tumor radiores ponse by multiple mechanisms that may involve direct and indirect actions o n tumor cell survival.